Bendamustine hydrochloride, chemically 5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazole-2-butanoic acid hydrochloride and has the structural formula:

Bendamustine Hydrochloride was initially synthesized in 1963 in the German Democratic Republic (GDR) and was available from 1971 to 1992 there under the tradename Cytostasan®. Since that time, it has been marketed in Germany under the tradename Ribomustin®. Bendamustine hydrochloride is currently available in the United States under the tradename Treanda® (Cephalon, Inc., Frazer, Pa.). Bendamustine is an alkylating agent that has been shown to have therapeutic utility in treating diseases such as chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and breast cancer.
A process for the preparation of 1H-benzimidazol-1-methyl-5-N,N-di-(2-hydroxyethyl) amino-2-butanoic acid ethyl ester was reported in Journal of pract.chem 20, 178-186, (1963). According to the journal also reported a process for the preparation of bendamustine hydrochloride.
A process for the preparation of 1H-benzimidazol-1-methyl-5-N,N-di-(2-hydroxyethyl) amino-2-butanoic acid ethyl ester was reported in Chinese Journal of new drugs 2007, Vol. 16(23), 1960-63. According to the journal also reported a process for the preparation of bendamustine hydrochloride.
We have found that an improved process for the preparation of 1H-benzimidazol-1-methyl-5-N,N-di-(2-hydroxyethyl) amino-2-butanoic acid ethyl ester.
We have also found that an improved process for the preparation of bendamustine hydrochloride.
4-(7, 8-dihydro-6-(2-chloroethylamino)-3-methyl-1,4-thiazino[3,2-g]benzimidazoyl(2))-butyric acid is a potential impurity in bendamustine hydrochloride. The chemical formula of 4-(7,8-dihydro-6-(2-chloroethylamino)-3-methyl-1,4-thiazino[3,2-g]benzimidazoyl(2))-butyric acid may be represented as:

The present invention is intended to enhance the purity of bendamustine hydrochloride. In particular, the present invention is directed to reduce or remove 4-(7,8-dihydro-6-(2-chloroethylamino)-3-methyl-1,4-thiazino[3,2-g]benzimidazoyl(2))-butyric acid impurity from bendamustine hydrochloride.
We have also found that a novel process for purification of bendamustine hydrochloride.
Thus, one object of the present invention is to provide an improved process for the preparation of 1H-benzimidazol-1-methyl-5-N,N-di-(2-hydroxyethyl) amino-2-butanoic acid ethyl ester.
Another object of the present invention is to provide an improved process for the preparation of bendamustine hydrochloride.
Another object of the present invention is to provide a novel process for purification of bendamustine hydrochloride.